The invention relates to cationic polyamines for treatment of viral infections and methods thereof, and more specifically, to cationic modified polyethylenimines for anti-viral applications.
Treatment of viral infections continues to be elusive owing to the variance in virus structure (RNA, DNA, enveloped and non-enveloped viruses) together with their ability to rapidly mutate and acquire resistance. Viral diseases continue to be one of the leading causes of morbidity and mortality since ancient times. In recent years, viral infections have emerged as an eminent global public health problem mainly because of a rapid increase in human population, aging, climate change, and medical treatments that suppress the immune system, including irradiation therapy, anti-cancer chemotherapy and organ transplantation. For example, the worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003, dengue fever, and bird flu (e.g., H1N1) outbreaks in Asia over the last two decades have imposed an enormous economic burden. More recently, several new viral pathogens like Nipah virus, Chikungunya virus (CHIKV), and mutated pandemic bird flu virus (e.g., H7N9) have been found in the human population. Consequently, significant effort has been directed to develop vaccines and anti-viral drugs to control and eradicate viral infections. However, the rapid mutation of viruses (especially flu virus), due to inherent genomic instability, makes vaccinations inefficient. Moreover, for many viral infections (e.g., dengue and Chikungunya viruses) there are no clinical drugs available. Since there are so many types and subtypes of pathogenic viruses that easily mutate to form drug-resistant strains, controlling them individually has not been possible.
Viruses can be classified into DNA and RNA viruses according to the genes they hold, as well as enveloped and non-enveloped viruses. This shows the complexity of the problem in attempting to design a general anti-viral agent. Most emerging and re-emerging viruses belong to the RNA type, including flavivirus family (e.g., dengue virus, or DENV), influenza, CHIKV, Enterovirus 71 (EV 71), and SARS Co-V. Many of these viruses exploit an endosomal pathway to infect cells. The low pH of the endosome allows introduction of viral genomes into cytoplasm. Furthermore, a number of enveloped viruses utilize anionic phosphatidylserine (PS)/TIM (T cell/transmembrane, immunoglobulin, and mucin) receptor binding and/or the apoptotic cell clearance pathway for entry to cells. This suggests that masking TIM receptors may provide new avenues for controlling viral infection.
Due to the existence of cationic and anionic regions on the viral surface, charged polymers potentially provide a means of exploiting electrostatic interactions to inhibit viral infections. However, attempts to prevent viral infections using anionic polymers (e.g., sulfated polysaccharides such as dextran, xylofuranan, ribofuranan and curdlan) to bind with cationic charges on the viral surface met limited success.
Heparin, extracted from animals, has strong activity against dengue virus, but has limited utility since it is an anti-coagulant.
Cationic polymers including cationic acrylate polymers, polyethylenimines and cationic poly(phenylene ethylene) polymers can also potentially interact with anionic groups of the viral surface by non-specific electrostatic interactions.
Polyethylenimines (PEIs) are polyamines that are commercially available in a broad range of molecular weights. The PEIs are formed as either linear (LPEI) or branched (BPEI) macromolecules. PEIs have found many applications in products, such as detergents, adhesives, water treatment agents, and cosmetics. Due to their ability to enter a cell through the cell membrane, PEIs have been utilized as drug carriers in biomedical applications. Polycationic PEIs can mediate gene transfer into mammalian cells in vitro and in vivo as a complex with DNA. However, cationic polymers such as linear polyethylenimine (PEI) exhibit high non-specific cytotoxicity towards mammalian cells and induce hemolysis. Moreover, the linear PEI is less water soluble than branched PEI.
A number of viral infections are pH-dependent, where low pH in the endosome is required for replication. Recently, niclosamide, an FDA approved anti-helminthic compound, was reported to prevent infections of pH-dependent viruses by neutralizing the endosomal pH. However, its highest selectivity was only ˜24 against influenza virus (PR8) and human rhinovirus (HRV14). Ammonium chloride and chloroquine having pH neutralization ability were also reported to prevent viral infections, but they are highly toxic, limiting clinical applications.
An ongoing need exists for broad spectrum anti-viral agents that are non-hemolytic and that provide general and safe strategies to prevent viral infections. Anti-viral macromolecules with distinctive functional groups are needed to specifically bind to viral surface proteins as well as compete with viruses for immune cell/target cell binding to prevent infection.